A New Drug Design Targeting the Adenosinergic System for Huntington's Disease

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Title:	A New Drug Design Targeting the Adenosinergic System for Huntington's Disease
Authors:	ng, NK (Huang, Nai-Kuei) Lin, JH (Lin, Jung-Hsin) Lin, JT (Lin, Jiun-Tsai) Lin, CI (Lin, Chia-I) Liu, EMW (Liu, Eric Minwei) Lin, CJ (Lin, Chun-Jung) Chen, WP (Chen, Wan-Ping) Shen, YC (Shen, Yuh-Chiang) Chen, HM (Chen, Hui-Mei) Chen, JB (Chen, Jhih-Bin) Lai, HL (Lai, Hsing-Lin) Yang, CW (Yang, Chieh-Wen) Chiang, MC (Chiang, Ming-Chang) Wu, YS (Wu, Yu-Shuo) Chang, C (Chang, Chen) Chen, JF (Chen, Jiang-Fan) Fang, JM (Fang, Jim-Min) Lin, YL (Lin, Yun-Lian) Chern, YJ (Chern, Yijuang)
Contributors:	Grad Inst Biotechnol
Keywords:	DEPRIVATION-INDUCED APOPTOSIS RAT PHEOCHROMOCYTOMA CELLS SITE-DIRECTED MUTAGENESIS TRANSGENIC MOUSE MODEL A(2A) RECEPTOR AGONIST CENTRAL-NERVOUS-SYSTEM GASTRODIA-ELATA BLUME UREA CYCLE DEFICIENCY LIGAND RECOGNITION SERUM DEPRIVATION
Date:	2011-06-21
Issue Date:	2013-01-16 16:04:19 (UTC+8)
Abstract:	Background: Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. Methodology/Principal Findings: Here, we report a novel dual-function compound, N-6-(4-hydroxybenzyl) adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. Conclusions/Significance: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e. g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.
Relation:	PLOS ONE Volume: 6 Issue: 6 Article Number: e20934
Appears in Collections:	[Graduate Institute of Biotechnology ] journal articles

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